Step-by-step design of proteins for small molecule interaction: a review on recent milestones

Protein design is the field of synthetic biology that aims at developing de-novo custom made proteins and peptides for specific applications. Despite exploring an ambitious goal, recent computational advances in both hardware and software technologies have paved the way to high-throughput screening and detailed design of novel folds and improved functionalities. Modern advances in the field of protein design for small molecule targeting are described in this review, organized in a step-by-step fashion: from the conception of a new or upgraded active binding site, to scaffold design, sequence optimization and experimental expression of the custom protein. In each step, contemporary examples are described, and state-of-the art software is briefly explored.publishe

Antibacterial, Anti-HIV-1 Protease and Cytotoxic Activities of Aqueous Ethanolic Extracts from Combretum Adenogonium Steud. Ex A. Rich (Combretaceae).

\ud \ud Records have shown that Combretum adenogonium Steud. Ex A. Rich (Combretaceae) is used in traditional medicine systems of several tribes in Tanzania. This study focused on the investigation of antibacterial activity, anti-HIV-1 protease activity, toxicity properties and classes of phytochemicals in extracts from C. adenogonium Steud. Ex A. Rich (Combretaceae) to evaluate potential of these extracts for development as herbal remedies. Dried plant material were ground to fine powder and extracted using 80% aqueous ethanol to afford root, leaf and stem bark extracts. The extracts were assayed for anti-HIV-1 protease activities, antibacterial activities using microdilution methods and cytotoxicity using brine shrimps lethality assay. Screening for major phytochemical classes was carried out using standard chemical tests. All extracts exhibited antibacterial activity to at least one of the test bacteria with MIC-values ranging from 0.31-5.0 mg/ml. Two extracts, namely, root and stem bark exhibited anti-HIV-1 PR activity with IC50 values of 24.7 and 26.5 μg/ml, respectively. Stem bark and leaf extracts showed mild toxicity with LC50 values of 65.768 μg/ml and 76.965 μg/ml, respectively, whereas roots were relatively non-toxic (LC50 = 110.042 μg/ml). Phytochemical screening of the extracts indicated presence of flavonoids, terpenoids, alkaloids, tannins, glycosides and saponins. These results provide promising baseline information for the potential development of C. adenogonium extracts in treatment of bacterial and HIV/AIDS-related opportunistic infections

HISTOLOGICAL AND BIOCHEMICAL EFFECTS OF ARTEETHERTM ON THE LIVER OF WISTAR RATS

ArteetherTM is among the recent drugs that are used to combat choroquine-resistant malarial parasites. This study examined the effects of arteetherTM on enzyme biomarkers of the liver, serum protein concentrations, and liver morphology. Twenty (20) adult albino Wistar rats weighing 200 – 250 g were randomly divided into four groups (A, B, C and D) of five animals each, and used in this study. Group A rats were given intramuscular (i. m.) arteetherTM (3 mg/kg b. w.) daily for 3 days. Group B rats received i. m. arteetherTM (6 mg/kg b. w.) daily for 3 days. Group C rats were given i. m. arteetherTM (3 mg/kg b. w.) daily for 3 days. The same dose was repeated at two-weekly intervals for 4 further weeks, while group D rats which received normal saline (0.9 % w/ v, 3 ml/kg b.w.), served as controls. At the end of the experiment, the body weights of the animals were determined and recorded. Serum levels of alanine transaminase (ALT), aspartate transaminase (ASP), alkaline phosphatase (ALP), total protein (TP) and albumin were assayed, and histological studies were performed. Results obtained show no significant difference (

An overview of anti-diabetic plants used in Gabon: Pharmacology and Toxicology

© 2017 Elsevier B.V. All rights reserved.Ethnopharmacological relevance: The management of diabetes mellitus management in African communities, especially in Gabon, is not well established as more than 60% of population rely on traditional treatments as primary healthcare. The aim of this review was to collect and present the scientific evidence for the use of medicinal plants that are in currect by Gabonese traditional healers to manage diabetes or hyperglycaemia based here on the pharmacological and toxicological profiles of plants with anti-diabetic activity. There are presented in order to promote their therapeutic value, ensure a safer use by population and provide some bases for further study on high potential plants reviewed. Materials and methods: Ethnobotanical studies were sourced using databases such as Online Wiley library, Pubmed, Google Scholar, PROTA, books and unpublished data including Ph.D. and Master thesis, African and Asian journals. Keywords including ‘Diabetes’ ‘Gabon’ ‘Toxicity’ ‘Constituents’ ‘hyperglycaemia’ were used. Results: A total of 69 plants currently used in Gabon with potential anti-diabetic activity have been identified in the literature, all of which have been used in in vivo or in vitro studies. Most of the plants have been studied in human or animal models for their ability to reduce blood glucose, stimulate insulin secretion or inhibit carbohydrates enzymes. Active substances have been identified in 12 out of 69 plants outlined in this review, these include Allium cepa and Tabernanthe iboga. Only eight plants have their active substances tested for anti-diabetic activity and are suitables for further investigation. Toxicological data is scarce and is dose-related to the functional parameters of major organs such as kidney and liver. Conclusion: An in-depth understanding on the pharmacology and toxicology of Gabonese anti-diabetic plants is lacking yet there is a great scope for new treatments. With further research, the use of Gabonese anti-diabetic plants is important to ensure the safety of the diabetic patients in Gabon.Peer reviewedFinal Accepted Versio

Ginger Stimulates Hematopoiesis via Bmp Pathway in Zebrafish

) has been widely used in traditional medicine; however, to date there is no scientific research documenting the potential of ginger to stimulate hematopoiesis. expression in the caudal hematopoietic tissue area. We further confirmed that Bmp/Smad pathway mediates this hematopoiesis promoting effect of ginger by using the Bmp-activated Bmp type I receptor kinase inhibitors dorsomorphin, LND193189 and DMH1.Our study provides a strong foundation to further evaluate the molecular mechanism of ginger and its bioactive components during hematopoiesis and to investigate their effects in adults. Our results will provide the basis for future research into the effect of ginger during mammalian hematopoiesis to develop novel erythropoiesis promoting agents

Evaluation of the antinociceptive and anti-inflammatory effects of the acetone extract from Anacardium occidentale L

The stem bark of Anacardium occidentale L. (Anacardiaceae), commonly called cashew, is used in Brazilian traditional medicine for the treatment of gastric and inflammatory disorders. The present study was carried out to investigate the in vivo anti-inflammatory activities of the acetone extract (AE) of the stem bark of A. occidentale. We evaluated the pharmacological activities of this plant material through the analgesic, antiedematogenic and chemotaxic inhibitory effects produced by the AE. The oral administration (p.o.) of mice with the AE (0.1, 0.3 and 1.0 g/kg) or positive control indomethacin (10 mg/kg) inhibited acetic acid-induced writhing by 18.9, 35.9, 62.9 and 68.9%, respectively (ID50% = 530 mg/kg). The highest dose of the AE was able to inhibit croton oil-induced ear edema formation by 56.8% (indomethacin at 10 mg/kg, p.o. - 57.6% inhibition). When submitted to the carrageenan-induced peritonitis test, the AE (0.1, 0.3 and 1.0 g/kg, p.o.) impaired leukocyte migration into the peritoneal cavity by 24.8, 40.5 and 49.6%, respectively. The positive control, dexamethasone (2 mg/kg, s.c.), inhibited leukocyte migration by 66.9%. These results indicate the presence of anti-inflammatory and antinociceptive principles in the acetone extract of Anacardium occidentale, and reinforce the plant's potential therapeutic use against pain and inflammatory diseases.As cascas do caule do Anacardium occidentale L. (Anacardiaceae), conhecido como cajueiro, são popularmente utilizadas no Brasil para o tratamento de doenças gástricas e inflamatórias. Este estudo teve como objetivo a avaliação farmacológica in vivo da atividade antiinflamatória do extrato acetônico (AE) obtido das cascas do A. occidentale, investigando os efeitos analgésico, antiedematogênico e inibitório sobre a quimiotaxia deste material botânico. A administração oral (p.o.) em camundongos com o AE (0,1; 0,3 e 1 g/kg) ou o controle positivo indometacina (10 mg/kg) inibiu as contorções abdominais induzidas pelo ácido acético em 18,9; 35,9; 62,9 e 68,9% respectivamente (ID50% = 530 mg/kg). Esta maior dose do AE também inibiu o edema de orelha produzido pelo óleo de cróton em 56,8% (indometacina, 10 mg/kg, p.o. - 57,6% de inibição). No teste da peritonite induzido pela carragenina, o AE (0,1; 0,3; e 1,0 mg/kg, p.o.) reduziu a migração de leucócitos para a cavidade peritoneal em 24,8; 40,5; e 49,6% respectivamente, enquanto que o controle positivo dexametasona (2 mg/kg, s.c.) inibiu a migração de leucócitos em 66,9%. Estes resultados indicam a presença de princípios ativos antiinflamatórios e antinociceptivos no extrato acetônico de Anacardium occidentale e reforçam o potencial terapêutico da planta em doenças que envolvem dor e inflamação

Studies on the pharmacology of some antimalarial drugs

Pharmacological studies of the antimalarial drugs chloroquine, primaquine, quinine, progtianil and pyrimethamine have been made. These studies have shown that the compounds possess a wide spectrum of pharmacological actions in common on many tissues and organ-systems. In most cases, their effects were biphasic, consisting of an initial stimulation followed by a more permanent inhibitory phase. All five antimalarial compounds, at low concentrations, reduced the base-line tone (tension) of all smooth muscles studied, and augmented electrically-induced contractions of the chick oesophagus, vas deferens and central ear artery preparations. Higher concentrations of the drugs dose-dependently contracted gastrointestinal smooth muscles and inhibited the spontaneous, myogenic rhythmic contractions of intestinal muscles, uterine strips and portal veins in vitro in a dose-dependent manner. In the same dose range they inhibited the electrically-evoked contractions of the chick oesophagus, vas deferens and central ear artery preparations. The drugs relaxed tracheal chain preparations contracted with acetylcholine (in the presence of physostigmine), carbachol, histamine and 5-hydroxytryptamine. In vitro, all five compounds antagonised the actions of standard spasmogens in all preparations examined. This spasmolytic effect of the drugs has been shown to be non-specific in nature. All the five compounds, in very low dosos, augmented the action of acetylcholine on frog rectus abdominis and chick biventer-cervicis muscles. High concentrations of the drugs themselves caused dose-related sustained contractions of the muscles in vitro. In similar concentrations they inhibited, or abolished, the actions of acetylcholine, carbachol, nicotine and potassium chloride. In some cases, low concentrations of the compounds, especially quinine, chloroquine and primaquine, augmented electrically-induced twitches of the chick biventer and rat hemi-diaphragm muscles in vitro, and of the soleus and tibialis anterior muscles of the cat in vivo. High doses of the compounds, themselves inhibited the twitches in a dose-related manner, and augmented the effects of neuromuscular blocking agents on the preparations. The drugs also inhibited tho tetanic as well as the intra-arterially injected acetylcholine- induced contractions of the tibialis anterior muscle in vivo. All the five compounds possessed anticholinesterase activity. In isolated cardiac muscle, all the five drugs studied increased the refractory period and caused negative inotropic and chronotropic responses. However, low concentrations of the quinoline compounds (primaquine, chloroquine and quinine) induced slight but measurable transient positive inotropic and chronotropic affects in the heart. Intravenous injections of each of the five compounds into anaesthetized cats produced similar cardiovascular changes. Those changes consisted of dose-dependent reductions in systemic and pulmonary arterial pressures, left ventricular pressure, left ventricular dP/dt max; and heart rate. Other changes consisted of dose-related increases in right atrial and left ventricular, end-diastolic pressures, P-R interval and QRS complex duration. All the compounds inhibited or abolished the pressor effects of intravenous noradrenaline on the cardiovascular system.Pharmacological studies of the antimalarial drugs chloroquine, primaquine, quinine, progtianil and pyrimethamine have been made. These studies have shown that the compounds possess a wide spectrum of pharmacological actions in common on many tissues and organ-systems. In most cases, their effects were biphasic, consisting of an initial stimulation followed by a more permanent inhibitory phase. All five antimalarial compounds, at low concentrations, reduced the base-line tone (tension) of all smooth muscles studied, and augmented electrically-induced contractions of the chick oesophagus, vas deferens and central ear artery preparations. Higher concentrations of the drugs dose-dependently contracted gastrointestinal smooth muscles and inhibited the spontaneous, myogenic rhythmic contractions of intestinal muscles, uterine strips and portal veins in vitro in a dose-dependent manner. In the same dose range they inhibited the electrically-evoked contractions of the chick oesophagus, vas deferens and central ear artery preparations. The drugs relaxed tracheal chain preparations contracted with acetylcholine (in the presence of physostigmine), carbachol, histamine and 5-hydroxytryptamine. In vitro, all five compounds antagonised the actions of standard spasmogens in all preparations examined. This spasmolytic effect of the drugs has been shown to be non-specific in nature. All the five compounds, in very low dosos, augmented the action of acetylcholine on frog rectus abdominis and chick biventer-cervicis muscles. High concentrations of the drugs themselves caused dose-related sustained contractions of the muscles in vitro. In similar concentrations they inhibited, or abolished, the actions of acetylcholine, carbachol, nicotine and potassium chloride. In some cases, low concentrations of the compounds, especially quinine, chloroquine and primaquine, augmented electrically-induced twitches of the chick biventer and rat hemi-diaphragm muscles in vitro, and of the soleus and tibialis anterior muscles of the cat in vivo. High doses of the compounds, themselves inhibited the twitches in a dose-related manner, and augmented the effects of neuromuscular blocking agents on the preparations. The drugs also inhibited tho tetanic as well as the intra-arterially injected acetylcholine- induced contractions of the tibialis anterior muscle in vivo. All the five compounds possessed anticholinesterase activity. In isolated cardiac muscle, all the five drugs studied increased the refractory period and caused negative inotropic and chronotropic responses. However, low concentrations of the quinoline compounds (primaquine, chloroquine and quinine) induced slight but measurable transient positive inotropic and chronotropic affects in the heart. Intravenous injections of each of the five compounds into anaesthetized cats produced similar cardiovascular changes. Those changes consisted of dose-dependent reductions in systemic and pulmonary arterial pressures, left ventricular pressure, left ventricular dP/dt max; and heart rate. Other changes consisted of dose-related increases in right atrial and left ventricular, end-diastolic pressures, P-R interval and QRS complex duration. All the compounds inhibited or abolished the pressor effects of intravenous noradrenaline on the cardiovascular system